rs187002252

Positions:

• chr12-51762497-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014191.4(SCN8A):​c.2371-6A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000488 in 1,612,584 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00046 (5 hom.)
• Consequence: SCN8A NM_014191.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003593
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.306

Genes affected

SCN8A (HGNC:10596): (sodium voltage-gated channel alpha subunit 8) This gene encodes a member of the sodium channel alpha subunit gene family. The encoded protein forms the ion pore region of the voltage-gated sodium channel. This protein is essential for the rapid membrane depolarization that occurs during the formation of the action potential in excitable neurons. Mutations in this gene are associated with cognitive disability, pancerebellar atrophy and ataxia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 12-51762497-A-G is Benign according to our data. Variant chr12-51762497-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 139070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-51762497-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000756 (115/152200) while in subpopulation EAS AF= 0.0162 (84/5190). AF 95% confidence interval is 0.0134. There are 0 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 115 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SCN8A	NM_001330260.2	c.2371-6A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000627620.5	NP_001317189.1
SCN8A	NM_014191.4	c.2371-6A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000354534.11	NP_055006.1
SCN8A	NM_001177984.3	c.2371-6A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001171455.1
SCN8A	NM_001369788.1	c.2371-6A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001356717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCN8A	ENST00000354534.11	c.2371-6A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_014191.4	ENSP00000346534	P4
SCN8A	ENST00000627620.5	c.2371-6A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001330260.2	ENSP00000487583	A1

Frequencies

GnomAD3 genomes AF: 0.000776 AC: 118 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0167

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00154 AC: 383 AN: 248024 Hom.: 2 AF XY: 0.00139 AC XY: 187 AN XY: 134622

Gnomad AFR exome AF: 0.000390

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0203

Gnomad SAS exome AF: 0.000197

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000999

GnomAD4 exome AF: 0.000460 AC: 672 AN: 1460384 Hom.: 5 Cov.: 31 AF XY: 0.000464 AC XY: 337 AN XY: 726500

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.0000674

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0129

Gnomad4 SAS exome AF: 0.000372

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.000756 AC: 115 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.000900 AC XY: 67 AN XY: 74432

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0162

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000253 Hom.: 0

Bravo AF: 0.000922

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 22, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 21, 2014	- -

Early infantile epileptic encephalopathy with suppression bursts Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.3
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000036
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs187002252; hg19: chr12-52156281;